Neutrophils are terminally differentiated cells with a lifespan of hours to days, terminated by programmed cell death, or apoptosis. In culture, apoptosis can be delayed by the addition of G-CSF or other growth factors or inflammatory mediators. We present preliminary data that neutrophils possess an acid endonuclease that is responsible for the internucleosomal cleavage seen in apoptosis. We have partially purified the endonuclease and show it has an apparent molecular weight of 35 kDa, a pH optimum of 5.5, and a threshold for activity of pH 6.8. In addition, we show that apoptotic neutrophils acidify to a pH value as low as pH 6.0 after G-CSF deprivation, and that pH homeostasis is dependent upon activity of the Na+/H+ exchanger (NHE) and the vacuolar-type proton ATPase. We propose to purify and clone the acid endonuclease and to examine the regulation of the NHE.